Studies have shown there to be a direct correlation between high serum-cholesterol levels and coronary heart disease. Cholesterol and triglycerides circulate in the plasma bound to proteins and are classified according to their density: very low-density lipoproteins (VLDL), low-density lipoproteins (LDL), or high-density lipoproteins (HDL). The HDL is the so-called "good" form of cholesterol, whereas the LDL is believed to be involved with the build-up of plaque in blood vessels.
Serum-cholesterol levels considered to be normal or acceptable vary with the age of individuals, but it is generally believed that levels in the range of 200 mg/dL are acceptable, meaning such an individual is not in a particularly high-risk category for coronary heart disease. Some reports indicate that nearly half the adults in the United States have concentrations of serum cholesterol that are above the optimal levels. Studies carried out in the 1980s also have shown that a reduction in the concentration of cholesterol-carrying lipoproteins can diminish the risk of heart disease.
Currently, known bile acid sequestering agents require large doses (colestipol 15-30 grams/day and cholestyramine 4-24 grams/day), and these agents cannot be administered in their dry form. The colestipol resin is available as a powder that is dispersed in water or a beverage (COLESTID). The cholestyramine is available in a flavored bar form (CHOLYBAR-Parke-Davis) and as a dispersible powder (QUESTRAN-Mead Johnson)..sup.1
Several drug therapies for reducing serum-cholesterol levels exist, including cholestyramine and colestipol, which are bile acid sequestering agents acting in the gastrointestinal tract and not absorbed into the body, as well as small molecules, such as dextrothyroxine sodium, clofibrate, probucol, gemfibrozil, and lovastatin which are absorbed into the body and act through altering the synthesis, metabolism and/or distribution of cholesterol in the body.
Cyclodextrins (CD) given orally have been shown to have lipid lowering activity and bile acid binding capabilities in vitro..sup.2,3,4 However, when .beta.-CD is administered orally, insignificant amounts are absorbed throughout the gastrointestinal tract. Most of the cyclodextrin is metabolized by the microflora in the colon. The metabolites are further metabolized and are finally excreted as carbon dioxide and water..sup.5 This extensive digestive and metabolizing capability of the gastrointestinal tract also eliminates the effectiveness of other bile binding compounds such as proteins (e.g., albumin and antibodies) and lipids (such as triglycerides) when administered orally.
The present invention discloses an improved formulation which is useful in lowering serum-cholesterol levels; the formulation comprising a bile acid binding resin or bile acid sequestering agent in combination with one or more bile acid binding materials. The formulation of the present invention provides an improvement over the known bile acid sequestering agents in that the formulation of the present invention is much more efficient and stable in binding bile acids and thereby reducing the quantity of formulation that must be administered.